title: Cardio-metabolic effectsof HIV protease inhibitors (lopinavir/ritonavir).
abstract: Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term side effects may include the onset of insulin resistance and cardiovascular diseases. However, the underlying molecular mechanisms responsible for highly active antiretroviral therapy (HAART)-induced cardio-metabolic effects are poorly understood. In light of this, we hypothesized that HIV protease inhibitor (PI) treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the ubiquitin proteasome system (UPS), thereby attenuating cardiac function. Lopinavir/Ritonavir was dissolved in 1% ethanol (vehicle) and injected into mini-osmotic pumps that were surgically implanted into Wistar rats for 8 weeks vs. vehicle and sham controls. We subsequently evaluated metabolic parameters, gene/protein markers and heart function (ex vivo Langendorff perfusions). PI-treated rats exhibited increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. In parallel, there was upregulation of hepatic gene expression, i.e. acetyl-CoA carboxylase b and 3-hydroxy-3-methylglutaryl-CoA-reductase, key regulators of fatty acid oxidation and cholesterol synthesis, respectively. PI-treated hearts displayed impaired cardiac contractile function together with attenuated UPS activity. However, there was no significant remodeling of hearts exposed to PIs, i.e. lack of ultrastructural changes, fibrosis, cardiac hypertrophic response, and oxidative stress. Western blot analysis of PI-treated hearts revealed that perturbed calcium handling may contribute to the PI-mediated contractile dysfunction. Here chronic PI administration led to elevated myocardial calcineurin, nuclear factor of activated T-cells 3 (NFAT3), connexin 43, and phosphorylated phospholamban, together with decreased calmodulin expression levels. This study demonstrates that early changes triggered by PI treatment include increased serum LDL-cholesterol levels together with attenuated cardiac function. Furthermore, PI exposure inhibits the myocardial UPS and leads to elevated calcineurin and connexin 43 expression that may be associated with the future onset of cardiac contractile dysfunction.
authors.affiliation: Cardio-Metabolic Research Group, Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Kathleen M S E
authors.initials: KM
authors.lastname: Reyskens
authors.forename: Tarryn-Lee
authors.initials: TL
authors.lastname: Fisher
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Schisler
authors.forename: Wendi G
authors.initials: WG
authors.lastname: O'Connor
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.forename: Cynthia
authors.initials: C
authors.lastname: Planesse
authors.forename: Florence
authors.initials: F
authors.lastname: Boyer
authors.forename: Philippe
authors.initials: P
authors.lastname: Rondeau
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bourdon
authors.forename: M Faadiel
authors.initials: MF
authors.lastname: Essop
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D018031:Connexin 43 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004338:Drug Combinations; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D061466:Lopinavir / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D019438:Ritonavir / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D019703:Calcineurin; D002135:Calcium-Binding Proteins; D008078:Cholesterol, LDL; D018031:Connexin 43; D017931:DNA Primers; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D061466:Lopinavir; D050778:NFATC Transcription Factors; D046988:Proteasome Endopeptidase Complex; D019438:Ritonavir; D014280:Triglycerides; D000099211:Phospholamban